Efficacy of antiviral therapy in reactivation prophylaxis in patients with Hepatitis B (HBV) infection treated with different immunosuppressive agents Deutsch M1, Manolakopoulos S1,Papadopoulos N2, Tsironi E3, Solomou A3, Skondra M1, Giannouli S1, Theohari M1 , Papatheodoridis GV1, Pectasides D1, Koskinas J1   12nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Greece 21st Department of Internal Medicine, 401 General Army Hospital of Athens, Greece 3 Gastroenterology Department, “Metaxa” General Hospital of Athens, Greece Abstract Mo1030

Background I HBV reactivation → represents the result of the loss of HBV immune control due to immunosuppression in a patient with inactive or “resolved” HBV infection → abrupt reappearance or increase in viral replication (rise in HBV DNA ± return of HBeAg) with liver damage (ALT increase → mild or very dramatic) → may progress to liver failure/death → depends on the initial HBV status, disease and the type of immunosupressive therapy → a special warning is issued in patients receiving anti-CD20 monoclonal antibodies ( Rituximab, Ofatumumab)

Background II Major societies management guidelines Agency Subspecialty Whom to screen Proposed screening AASLD Liver diseases All HBsAg, anti-HBc, anti-HBs EASL HBsAg, anti-HBc ACR Rheumatologists High risk patients before MTX or LEF No specific recommendations Expert Consensus Before anti-TNF/rituximab ASCO Oncologists Only high risk patients or high risk therapy HBsAg Consider anti-HBc AAD Dermatologists Patients on anti-TNF APAGE Gastroenterologists According to local practice (HBsAg, anti-HBc, anti-HBs) ECCO AGA Moderate to high risk patients

AGA guidelines (2015) of the prevention and treatment of hepatitis B reactivation during immunosupressive therapy – risk stratification VERY HIGH RISK (>20%) - HBsAg (+) + antiCD20 / HSCT HIGH RISK (11-20%) - HBsAg (+) + high dose CS / cytokine inhibitors (eg. antiCD52) MODERATE (1-10%) - HBsAg (+) + TNFs, cytotoxic without CS, anti-rejection Rx - HBsAg (-)/anti-HBc (+) + Rx with antiCD20 / HSCT LOW (<1%) - HBsAg (+) + MTX, AZA - HBsAg (-)/anti-HBc (+) + high dose CS / cytokine inhibitors (eg. antiCD52) VERY LOW (rare) - HBsAg (-)/anti-HBc (+) + TNFs, cytotoxic without CS, anti-rejection Rx, MTX, AZA Prophylaxis YES Prophylaxis NO

Choice of Antiviral Therapy as prophylaxis Background III Choice of Antiviral Therapy as prophylaxis Lamivudine (LAM) is still recommended in patients with low initial viral load (<2000IU/ml) and short duration (<12 mo) of immunosupression During LAM the emergence of resistant mutants in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV occur in 24% of immunocompetent patients (first year), 70% ( 5 years) and in 7.7% of immunosuppressed (1 year prophylactic therapy) Entecavir (ENT) and tenofovir disoproxil fumarate (TNF) can be considered in patients with initially high levels of HBV-DNA or those who will receive lengthy and repeated cycles of immunosupression The experience in this setting with ENT and TDF is limited

Aim The aim of the present study was to investigate the efficacy of prophylactic antiviral treatment with lamivudine (LAM), entecavir (ENT) or tenofovir (TDF) in patients receiving different immunosuppressive agents

Patients 110 immunosupressed patients retrospectively/prospectively included At least 6 months follow up HBV profile: HBsAg positive or HBsAg negative / anti-HBc positive with negative or positive anti-HBs Immunosuppressive therapy 1) conventional chemotherapy 2) therapy containing corticosteroids 3) containing monoclonals (rituximab/ofantumumab/alemtuzumab) Exclusion: HCV/delta or HIVco-infections NA’s →administered once daily in patients with normal renal function or dose adjusted according to the glomerular filtration rate (GFR)

Methods HBV DNA was measured with real time PCR (cut off 45 IU/ml) at presentation, at six months and at various times during follow-up along with liver biochemistry tests. HBV reactivation was defined as: >1 log increase in HBV DNA, or HBV DNA >2000 IU/ml if no baseline value was available, or Reverse-Seroconversion, with HBsAg detection when previously negative with or without acute hepatitis

Results Baseline characteristics of the patients Age, years 63.19±13 Gender (males), n(%) 60 (54.5) Median duration of follow-up, months 14,85 (6-156) Monoclonal regimens, n(%) 47 (43) Corticosteroids without monoclonal regimens, n(%) 23 (21) Conventional chemotherapy/other, n(%) 40 (36) HBV status HBsAg(+), n(%) 73 (66.5) antiHBc(+)/antiHBs(-), n(%) 20 (18) antiHBc(+)/antiHBs(+), n(%) 12 (11) not available, n(%) 5 (4.5)

Results: Patients without prophylaxis N=24 (22%) reactivation, n(%) 21 (87.5) Not screened n(%) 12 (50) HBsAg (+) n(%) 5 (20,8) HBsAg (-) n(%) 7 (29,2) Anti HBc (+) antiHBs(-) 3 (12,5) Anti HBc (+) antiHBs(+) 4 (16,7) Reverse seroconversion, n(%) 6 (66.5) 2 (8,3%) deaths HBsAg (+) with asthma receiving corticosteroids HbsAg (-) with chronic lymphocytic leukemia receiving Rituximab

Results: 21 patients with reactivation and no prophylaxis → treatment regimen % 1 death 1 death

Patients with prophylaxis: N=86 (78%): outcomes Results Patients with prophylaxis: N=86 (78%): outcomes ENT/TDF rescue 1 death (14%)

Results Patients who received prophylaxis : Characteristics according to the type of immunosuppression Treatment regimen HBV status Total=84* Conventional chemotherapy N=33 Corticosteroid based therapies without monoclonal N=22 Corticosteroid based therapies with monoclonal N=29 ENT/TDF HBsAg(+)/HBsAg(-)   19/2 13/3 7/12 ENT/TDF failure LAM 9/0 4/2 LAM failure 3/0 2/2 *2/86 patients received other immunosuppressive therapy and are not included

Characteristics(N% or mean±SD) antiHBc(+)antiHBs(+) Comparative data in patients receiving monoclonals versus other Characteristics(N% or mean±SD) Monoclonal YES N=45 Monoclonal NO N=65 P Gender M/F 32/13 28/37 0,08 Age 64,7±14,6 62,14±12 0,32 Reactivation 14 (31%) 10 (15,4%) 0,013 LAM failure 4 (15,8%) 3 (9,7%) 0,01 HBsAg (+) 26(31,6%) 58 (83,9%) 0,00 antiHBc(+) only 13(47,3%) 2 (3,2%) antiHBc(+)antiHBs(+) 5(21,1%) 3 (12,9%) 0,04 Follow up (months) 14±12 9,3±11,6 0,26 Patients with past HBV receiving monoclonals were statistically more often treated with prophylactic antivirals

Conclusions HBV reactivation may occur even in patients considered “low risk”(e.g : HBsAg negative treated with antiCD52) TDF and ENT are effective in prophylaxis and rescue treatment of HBV reactivation in patients receiving immunosupressive therapy LAM should not be the first choice especially in patients receiving monoclonal antibodies or corticosteroids even if they have initially negative HBsAg.

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